tbuckley/cabot-search huggingface dataset:
IL6 and CCL18 Mediate Cross-talk between <i>VHL</i>-Deficient Kidney Cells and Macrophages during Development of Renal Cell Carcinoma
Authors: Thi-Ngoc Nguyen, Hieu-Huy Nguyen-Tran, Chen-Yun Chen, Tien Hsu
Journal: Cancer Research (2022)

Abstract Loss of the von Hippel–Lindau (VHL) tumor suppressor gene function accounts for 70% to 80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises from sites of chronic inflammation, yet how ccRCC tumor cells interact with immune components of the microenvironment has not been fully elucidated. In this study, we used unbiased proteomic and genomic analyses on components of the tumor microenvironment under different conditions, identifying the molecular and cellular mechanisms that underlie the cross-talk between VHL-deficient kidney tubule cells and macrophages. In vitro and in a Vhlh conditional knockout mouse model, VHL-deficient noncancerous kidney epithelial cells, representing the early stage of ccRCC initiation, secreted IL6 that induced macrophage infiltration and polarization toward the protumorigenic M2 phenotype. Activated human macrophages secreted CCL18 and TGFβ1 to stimulate epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Treatment with IL6-neutralizing antibody rescued inflammatory, proliferative, and EMT phenotypes of kidney epithelial cells in Vhlh conditional knockout mice. Furthermore, in a human ccRCC xenograft model, exogenous human primary or cultured macrophages significantly promoted primary tumor growth and metastasis in a CCL18-dependent manner. These findings identify specific factors involved in reciprocal cross-talk between tumor cells and immune components in the microenvironment, thus providing an avenue for early intervention in ccRCC. Significance: The identification of VHL-deficient kidney tubule cell cross-talk with macrophages regulated by IL6 and CCL18 reveals potential targets for the prevention and treatment of ccRCC.
Abstract 265: Inhibiting proteasome in extracellular matrix (ECM) detached cells promotes anoikis
Authors: Funmilayo Adeshakin, Guizhong Zhang, Adeleye Adeshakin, Xiaochun Wan
Journal: Cancer Research (2022)

Abstract The underlying mediators for altered cell-extracellular matrix (ECM) communication in tumors remain to be understood and are likely to be multifactorial. Detached cells from the ECM are often cleared by a death process called ‘anoikis’. Anoikis is critical for health and homeostasis maintenance. However, aggressive cancer cells acquire anoikis resistance to promote invasion and metastasis in new sites. We previously identified metabolic reprogramming and upregulation of Vacuolar-ATPase members responsible for anoikis resistance while the manipulation of these pathways induced anoikis. However, the mechanisms underlying anoikis resistance and subsequent metastasis are yet to be fully elucidated, thus limiting anoikis-targeting drug exploration for metastasis control. Herein, our RNA-seq data revealed upregulated genes associated with proteasome activity (such as PSMA, PSMB, PSMD, and POMP) in ECM detached cancer cells compared to adherent cancer cells. Targeting this, using proteasome inhibitors (MG132 or bortezomib) in breast cancer, cervical, and melanoma cell lines sensitized cancer cells to anoikis through increased cellular, mitochondrial stress, and misfolded protein accumulation. Moreover, Bortezomib treatment in vivo in melanoma tumor model repressed metastasis. These data demonstrate proteasome activity is hijacked by ECM detached cancer cells to maintain proteostasis thus promoting anoikis resistance and metastasis. Regardless of the impressive outcome in treating hematological malignancies, proteasome inhibitors show little effect against solid tumors in several clinical trials that utilized selective and more potent inhibitors either as a single or in combinatory therapy. In this sense, our finding suggests proteasome inhibitors may be more attractive for metastasis control rather than local tumor treatment. Altogether, our findings demonstrate enhanced proteasome activity within the tumor cells is critical for anoikis resistance, and targeting this can markedly overcome resistance and control tumor metastasis. Citation Format: Funmilayo Adeshakin, Guizhong Zhang, Adeleye Adeshakin, Xiaochun Wan. Inhibiting proteasome in extracellular matrix (ECM) detached cells promotes anoikis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 265.
PET Imaging of Estrogen Receptors for Gynecological Tumors
Authors: Tetsuya Tsujikawa, Akira Makino, Tetsuya Mori, Hideaki Tsuyoshi, Yasushi Kiyono, Yoshio Yoshida, Hidehiko Okazawa
Journal: Clinical Nuclear Medicine (2022)

Abstract In the past few decades, PET with 18 F-FDG has been used for the diagnosis of gynecological malignancies and is considered to be superior to conventional imaging methods in diagnostic accuracy for detecting metastatic lesions and local recurrence and in evaluating the treatment response. On the other hand, several gynecological tumors, such as endometrial cancer and leiomyoma, and breast cancer are estrogen-dependent, in which estrogen is essential for their development and progression. 18 F-FES is an 18 F-labeled compound of estradiol, the most bioactive type of estrogen, and 18 F-FES PET has been well-established for diagnosis, staging, and posttherapeutic follow-up in patients with estrogen receptor–positive breast cancer. Compared with in vitro assessment of tumor biopsy material, PET imaging has the advantages of being able to measure in vivo tumor behavior, characterize the entire tumor burden, and capture the heterogeneity of the tumor phenotype. In this article, we review the phenotyping of estrogen-related gynecological tumors other than breast cancer using 18 F-FES PET and demonstrate the additional value of 18 F-FES PET to 18 F-FDG PET in their diagnosis and prognostication. Moreover, promising PET tracers other than 18 F-FES and 18 F-FDG for the evaluation of estrogen-related gynecological tumors are introduced.
Abstract 3962: Mechanisms of tumor recurrence and drug resistance in rhabdomyosarcoma
Authors: Devmini C. Moonamale, Marco Wachtel, Beat W. Schäfer
Journal: Cancer Research (2022)

Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma, which constitutes of two main histological subtypes. Alveolar Rhabdomyosarcoma (FP-RMS) is characterized by a fusion protein PAX3-FKHR, whereas embryonal Rhabdomyosarcoma (FN-RMS), which is the focus of this project, is more genetically heterogeneous. The prognosis for RMS has improved over the years, however the cure rates for recurrent or relapse disease remains dismal, warranting further identification of novel therapeutic interventions, which is the aim of this project. To this end, we performed two CRISPR knockout screens, using a kinome sgRNA library and a whole genome sgRNA library in combination with etoposide at a concentration of IC10, in order to identify genes that might confer resistance to chemotherapeutic drugs. In addition, the kinome screen was also designed to identify essential genes by using the treatment control samples as further time points. For treatment associated genes, we identified components of the JNK/P38 and Hippo signaling pathways among the top hits. We also found enrichment of a novel pathway involving HIFα stabilization via the genes LRRK2 and PTK6. Further and as expected, many DNA damage repair pathways were enriched. Finally in this category, players of the Wnt signaling pathway including JNK1, which is involved in non-canonical Wnt signaling were found to be enriched. As for essential gene identification, many cell cycle genes such as CDK6, PLK3 and PLK4 were among the top hits, as well as WEE1, which has been implicated in the context of RMS, were common between all the time points. Taken together, the CRISPR screens identified potential pathways that might be involved in resistance of FN-RMS cells towards etoposide. Selected candidates are being validated via an in vitro competition assay and drug screening is being performed to identify inhibitors that could be used to re-sensitize cells to treatment with standard chemotherapy. Citation Format: Devmini C. Moonamale, Marco Wachtel, Beat W. Schäfer. Mechanisms of tumor recurrence and drug resistance in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3962.
Waldenstrom Macroglobulinemia: Tailoring Therapy for the Individual
Authors: Morie A. Gertz
Journal: Journal of Clinical Oncology (2022)

With the introduction of multiple new effective therapeutic options for the treatment of macroglobulinemia, a structured approach to management of this rare lymphoma is currently needed. A review of phase II and III treatment trials over the past 20 years was performed, and high-quality trials are summarized in this manuscript. Because of the lack of large prospective trials comparing different classes of therapy, a uniform recommendation applicable to all patients cannot be made, and the approach must be individualized incorporating patient preferences, comorbidities, and the range of therapeutic toxicities. Therapeutic options for patients with newly diagnosed and previously treated macroglobulinemia are presented on the basis of the best available evidence in the literature.
Abstract 4156: BI-1808 - a first in class ligand-blocking αTNFR2 antibody for cancer immunotherapy
Authors: Linda Mårtensson, Kirsty Cleary, Petra Holmkvist, Mathilda Kovacek, Carolin Svensson, Monika Semmrich, Therese Blidberg, Mimoza Demiri, Osman Dadas, Marie Borggren, Vici Pitic, Sean H. Lim, Stephen A. Beers, Susanne Gertsson, Kristoffer S. Rohrberg, Ingrid Karlsson, Andres McAllister, Mark S. Cragg, Björn Frendeus, Ingrid Teige
Journal: Cancer Research (2022)

Abstract The pleiotropic TNF-α:TNFR axis plays a central role in immune regulation. While the cellular expression of TNFR1 is broad, TNFR2 expression is mainly restricted to immune cells. The therapeutic potential of targeting TNFR2 for cancer treatment has been previously indicated and to gain further insight, we generated a wide panel of TNFR2-specific antibodies using the n-CoDeR F.I.R.S.T™ target and antibody discovery platforms. We identified antibodies against mouse or human TNFR2 that could block TNF-α binding and showed potent anti-tumor activity in several immune-competent models, both as single agent and in combination with anti-PD1. The mechanism-of-action was shown to be FcγR dependent and likely mediated through a combination of intra-tumor T reg depletion, CD8+ T cell expansion and modulation of innate immune cells e.g. neutrophils and myeloid cells. Toxicological studies of the human lead-candidate BI-1808 in non-human primates (NHP) demonstrated very good tolerability at doses up to 200 mg/kg, and in vitro studies with human cells showed no signs of harmful cytokine release. Furthermore, in vivo studies using immune competent mouse cancer experimental models showed a clear relationship between dose, receptor occupancy (RO) and efficacy. In both murine models and in the NHPs, soluble TNFR2 was clearly modulated by the treatment and closely correlated with RO. In addition, several changes in the immune cells (e.g. T cells and neutrophils) in the blood compartment were observed. Since January 2021, BI-1808 is evaluated in an ongoing Phase I/IIa trial. Similar to the preclinical studies, correlations between dose, RO and soluble TNFR2 has been clearly observed in the patients. In addition, and consistent with TNF-α:TNFR biology being conserved across the species, modulations of T cell and neutrophil numbers are also paralleled between the patients, NHPs and mice, increasing the likelihood of successful clinical translation of our findings. Citation Format: Linda Mårtensson, Kirsty Cleary, Petra Holmkvist, Mathilda Kovacek, Carolin Svensson, Monika Semmrich, Therese Blidberg, Mimoza Demiri, Osman Dadas, Marie Borggren, Vici Pitic, Sean H. Lim, Stephen A. Beers, Susanne Gertsson, Kristoffer S. Rohrberg, Ingrid Karlsson, Andres McAllister, Mark S. Cragg, Björn Frendeus, Ingrid Teige. BI-1808 - a first in class ligand-blocking αTNFR2 antibody for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4156.
Abstract 5166: Blood-based biomarker analysis for predicting efficacy of definitive concurrent chemoradiotherapy and durvalumab consolidation in patients with unresectable locally advanced non-small cell lung cancer
Authors: Cheol-Kyu Park, Hwa-Kyung Park, Hyung-Joo Oh, Hyun-Ju Cho, In-Jae Oh, Young-Chul Kim
Journal: Cancer Research (2022)

Abstract Background: This study aimed to investigate the feasibility of using circulating tumor cells (CTCs) and peripheral blood cells (PBCs) as biomarkers for predicting the efficacy of concurrent chemoradiotherapy (CCRT) and durvalumab consolidation (DC) in patients with locally advanced non-small cell lung cancer (NSCLC). Methods: We recruited patients diagnosed with unresectable stage III NSCLC who received definitive CCRT between March 2020 and March 2021. DC was permitted in patients who did not progress after CCRT and tumor PD-L1 ≥1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated using CD-PRIME࣪ system, exhibited EpCAM/CK+/CD45− phenotype in BioViewCCBS࣪. Results: A total of 50 patients were enrolled and 23 patients received DC. The median duration of follow-up was 16.3 months, and the median progression-free survival (PFS) was not significantly different between patients with and without DC (13.1 vs. 13.5 months; p=0.355). In overall, patients with higher platelets (PLThi, &amp;gt;252x103/uL) at C1 had worse median PFS than those with lower platelets (PLTlo, ≤252x103/uL) (5.9 vs. 15.1 months; p&amp;lt;0.001). In DC group, patients with residual CTC clusters after CCRT (C1) had worse median PFS than those without detectable CTC cluster (9.5 vs. not reached; p=0.034). In multivariate analysis, PLThi at C1 was an independent factor for PFS (hazard ratio [HR] 4.12, 95% confidence interval [CI] 1.77-9.61; p=0.001), and patients with DC who had PLThi and residual CTC clusters at C1 showed the worst PFS (2.6 months, HR 44.40; p=0.001), even worse than those without DC who had PLThi (5.9 months, HR 15.65; p=0.002). Conclusions: Comprehensive analysis of CTC and PBC counts before and after CCRT, especially CTC clusters and platelets at C1, demonstrated they might be biomarkers for predicting survival. This finding could aid in risk stratification of patients with unresectable stage III NSCLC who are eligible for DC after definitive CCRT. Citation Format: Cheol-Kyu Park, Hwa-Kyung Park, Hyung-Joo Oh, Hyun-Ju Cho, In-Jae Oh, Young-Chul Kim. Blood-based biomarker analysis for predicting efficacy of definitive concurrent chemoradiotherapy and durvalumab consolidation in patients with unresectable locally advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5166.
Abstract 6326: Reshaping immune lung populations to inhibit pulmonary fibrosis and cancer by activation of purinergic receptor P2RX7
Authors: Serena Janho dit Hreich, Alina Ghinet, Valérie Vouret-Craviari
Journal: Cancer Research (2022)

Abstract Lung cancer is the most prevalent cancer worldwide with high mortality rate despite recent advances in therapies. Not only is fibrosis a major hallmark of lung cancer, it is also a risk factor for lung cancer development (mainly non-small cell lung cancer). In fact, patients diagnosed with idiopathic pulmonary fibrosis (IPF) are very likely to develop lung cancer. However, treatment and outcome of lung cancer patients with IPF is different than those without IPF despite their common genetic, molecular, cellular and immune properties. New therapeutic strategies are needed for improving outcome of patients bearing both diseases. To address this, we proposed that boosting the activation of P2RX7 with a positive modulator (HEI3090) would be a novel strategy to fight lung cancer. P2RX7 is a purinergic receptor activated by high extracellular ATP levels found in inflamed and tumor sites. It has anti-tumor and immunomodulatory properties by its ability to induce cell death and the release of IL-1b and IL-18. We showed previously that HEI3090 inhibits lung tumor growth by triggering an anti-tumor immune response that relies on IL-18. Indeed, HEI3090-release of IL-18 enhanced the cytotoxicity of NK cells and favored a Th1-biased immune response. Given that lung fibrosis is partly driven by inflammation with a dysregulated Th1/Th2/Th17 ratios and given the ability of HEI3090 to favor a Th1-biased immune response, we wondered if HEI3090 was able to inhibit fibrosis. To do so, we used the bleomycin mouse model where we show that activation of P2RX7 with HEI3090 inhibits lung fibrosis. HEI3090 targets P2RX7-expressing immune cells, decreases lung inflammation and favors an anti-fibrotic immune signature. Indeed, HEI3090 promotes the production of IFN-g by T cells and decreases pro-fibrotic IL-17A release by Th17 cells. Moreover, production of TGF-b, the key cytokine driving fibrosis, was greatly reduced in immune cells in HEI3090-treated mice. The antifibrotic effect of HEI3090 seems to rely on an increase of IL-18, known to induce the production of IFN-g by T cells. Overall, we show that reshaping lung immune phenotype by activation of P2RX7 is a promising strategy in lung fibrosis. HEI3090’s effect on cancer-related fibrosis is ongoing on a Kras mouse model. We highlight a new therapeutic strategy for patients with IPF that would ameliorate treatment and outcome of patients with both lung cancer and fibrosis Citation Format: Serena Janho dit Hreich, Alina Ghinet, Valérie Vouret-Craviari. Reshaping immune lung populations to inhibit pulmonary fibrosis and cancer by activation of purinergic receptor P2RX7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6326.
EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma
Authors: April A. Apfelbaum, Feinan Wu, Allegra G. Hawkins, Brian Magnuson, Jennifer A. Jiménez, Sean D. Taylor, Emma D. Wrenn, Olivia Waltner, Elise R. Pfaltzgraff, Jane Y. Song, Cody Hall, Deneen M. Wellik, Mats Ljungman, Scott N. Furlan, Russell J.H. Ryan, Jay F. Sarthy, Elizabeth R. Lawlor
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Propagation of Ewing sarcoma requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes Ewing sarcoma metastatic phenotypes, influences EWS::FLI1 transcriptional activity. Experimental Design: Existing tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR interference were employed to identify enhancers. CUT&amp;RUN and RNA sequencing defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by gene set enrichment, flow cytometry, and migration assays. Results: We found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of Ewing sarcoma cells along a mesenchymal axis. Conclusions: Ewing sarcoma tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13. See related commentary by Weiss and Bailey, p. 4360
Biofabrication of Multiplexed Electrochemical Immunosensors for Simultaneous Detection of Clinical Biomarkers in Complex Fluids
Authors: Sanjay S. Timilsina, Mohanraj Ramasamy, Nolan Durr, Rushdy Ahmad, Pawan Jolly, Donald E. Ingber
Journal: Advanced Healthcare Materials (2022)

Simultaneous detection of multiple disease biomarkers in unprocessed whole blood is considered the gold standard for accurate clinical diagnosis. Here, this study reports the development of a 4-plex electrochemical (EC) immunosensor with on-chip negative control capable of detecting a range of biomarkers in small volumes (15 µL) of complex biological fluids, including serum, plasma, and whole blood. A framework for fabricating and optimizing multiplexed sandwich immunoassays is presented that is enabled by use of EC sensor chips coated with an ultra-selective, antifouling, and nanocomposite coating. Cyclic voltammetry evaluation of sensor performance is carried out by monitoring the local precipitation of an electroactive product generated by horseradish peroxidase linked to a secondary antibody. EC immunosensors demonstrate high sensitivity and specificity without background signal with a limit of detection in single-digit picogram per milliliter in multiple complex biological fluids. These multiplexed immunosensors enable the simultaneous detection of four different biomarkers in plasma and whole blood with excellent sensitivity and selectivity. This rapid and cost-effective biosensor platform can be further adapted for use with different high affinity probes for any biomarker, and thereby create for a new class of highly sensitive and specific multiplexed diagnostics.